Amnion putty for cartilage repair

ABSTRACT

There are disclosed compositions for achieving reverse phase characteristics, methods of preparation thereof, and the use of amniotic tissue for cartilage repair. In an embodiment, a biocompatible articular tissue repair composition may have a therapeutic material and a carrier configured for achieving reverse phase characteristics, and methods for using the composition. In various embodiments, the therapeutic material may be amniotic tissue. In various embodiments, the carrier may be a poloxamer such as poloxamer 407. Other embodiments are also disclosed.

REFERENCE TO PENDING PRIOR PATENT APPLICATION

This application claims the benefit under 35 U.S.C. 119 (e) of U.S.Provisional Patent Application No. 62/476,454, filed Mar. 24, 2017 byRobert L. Bundy for “AMNION PUTTY FOR CARTILAGE REPAIR,” which patentapplication is hereby incorporated herein by reference.

BACKGROUND

Chondral defects and osteoarthritis in all articulating joints in thehuman body continue to present major challenges for the orthopedicsurgeon because of the limited healing potential of articular cartilage.Several different therapeutic methods are currently being used to repairdamaged cartilage. Current methods include, but are not necessarilylimited to, implantation of chondrocytes, whether they be juvenile oradult, via a patch or putty; fresh allograft chondral plugs; surgicalmicrofracture to stimulate cartilage growth; and amniotic fluidinjections. Generally, all of these fall short in regenerating hyalinecartilage.

SUMMARY

This Summary is provided to introduce a selection of concepts in asimplified form that are further described below in the DetailedDescription. This Summary is not intended to identify key aspects oressential aspects of the claimed subject matter. Moreover, this Summaryis not intended for use as an aid in determining the scope of theclaimed subject matter.

In an embodiment, there is provided a biocompatible articular cartilagetissue repair composition, comprising amniotic tissue, and a reversephase mixture of poloxamer and water, wherein the composition exhibitsreverse phase behavior and is non-liquid at ambient and bodytemperatures.

In one embodiment, the poloxamer is poloxamer 407.

In an embodiment, the mixture of poloxamer and water is 25 percentweight poloxamer and 75 percent weight water.

In another embodiment, the composition is 30 percent weight amniotictissue and 70 percent weight poloxamer and water.

In another embodiment, wherein the composition is 50 percent weightamniotic tissue and 50 percent weight poloxamer and water.

In yet another embodiment, there is provided a method to repaircartilage tissue, the method comprising providing a biocompatiblecartilage repair composition, comprising amniotic tissue, and a reversephase mixture of poloxamer and water, wherein the composition exhibitsreverse phase behavior and is non-liquid at ambient and bodytemperatures; and placing the composition in a cartilage defect of amammal.

In one embodiment, the method includes the step of placing thecomposition in the cartilage defect of a mammal includes placing thecomposition in a liquid state at a given temperature below the ambientand body temperatures.

In an embodiment, the method includes the step of placing thecomposition in the cartilage defect of a mammal includes allowing thecomposition to transition to a non-liquid at the ambient and bodytemperatures so as to resist displacement from the cartilage defect.

In still another embodiment, there is disclosed a biocompatiblearticular cartilage tissue repair composition, comprising a reversephase mixture of poloxamer and amniotic fluid; wherein the compositionexhibits reverse phase behavior and is non-liquid at ambient and bodytemperatures.

Other embodiments are also disclosed.

Additional objects, advantages and novel features of the technology willbe set forth in part in the description which follows, and in part willbecome more apparent to those skilled in the art upon examination of thefollowing, or may be learned from practice of the technology.

DETAILED DESCRIPTION

Embodiments are described more fully below in sufficient detail toenable those skilled in the art to practice the system and method.However, embodiments may be implemented in many different forms andshould not be construed as being limited to the embodiments set forthherein. The following detailed description is, therefore, not to betaken in a limiting sense.

Through literature research, it is documented that the anabolic andanticatabolic effects of a variety of growth factors have demonstratedpotential in both in vitro and animal studies of cartilage injury andrepair. Key chondrogenic factors are:

-   -   TGF-β1,3: Promotes chondrogenic differentiation and regulates        type II collagen expression.    -   BMP2,4,7: Induces chondrogenesis of MSC's and stimulates ECM        production by chondrocytes.    -   bFGF: Stimulates proliferation of chondrocytes.    -   IGF-1: Induces ECM synthesis.

Members of the transforming growth factor-β superfamily, fibroblastgrowth factor family and insulin-like growth factor-I have all beeninvestigated as possible treatment augments in the management ofchondral injuries and early osteoarthritis. Also, proteomic studies ofamniotic tissue show that the placenta has substantial number of growthfactors such as, but not limited to, bFGF, BMP-2, EGF, PDGF-AA, PDGF-BB,TGF-β1, FGF, VEGF, CTGF, and IGF.

Amniotic tissue has benefits as an implantable material. Amniotic tissuecontains substantial number of growth factors needed in cartilageregeneration. The challenge is keeping the amniotic tissue in placewhile its therapeutic value can take hold in an articulating jointfilled with synovial fluid.

Various embodiments herein provide an articulating cartilage repaircomposition which stimulates the body's own mesenchymal stem cells todifferentiate into chondrocytes thus repairing the cartilage defect. Inembodiments, this may be a formulation that is easily to apply to acartilage defect in either an open or endoscopic procedure, and whichremains at the site once placed.

In an embodiment, there is disclosed a biocompatible composition tofacilitate repair of articulating cartilage. The composition may includeamniotic tissue, and, a carrier comprising a means of achieving reversephase thermodynamic characteristics when mixed or otherwise combinedwith amniotic tissue. The composition is configured to resistdisplacement once implanted inasmuch as the composition is substantiallyliquid at 0° C. (i.e., at lower temperature than ambient or bodytemperature) and substantially more viscous at 35° C. (i.e., at highertemperature than liquid phase; ambient or body temperatures.)

A poloxamer, such as poloxamer 407, may be used to achieve reverse phasecharacteristics in a dispersed configuration in a biocompatible solventsuch as sterile water. Preferably the total carrier comprises a carrierof 25 weight percent of the poloxamer 407 dispersed in 75 weight percentof a biocompatible solvent. To vary the consistency of the composition,the weight percentage of amniotic tissue can be varied relative to theweight percentage of the carrier. For example, a paste-like form of thecomposition comprises 50 weight percent of amniotic tissue and 50 weightpercent of a carrier. A gel-like embodiment of the composition comprises30 weight percent of amniotic tissue and 70 weight percent of a carrier.Amniotic tissue may be pre-treated in a number of ways prior to theaddition of the carrier. Pre-treatment may include various amounts ofcutting, blending, chopping or mixing the amniotic tissue either aloneor with the carrier material. The amniotic tissue may be treated toremove or add constituents either before or after addition of thecarrier.

Also disclosed is a method to the development of cartilage tissue, themethod includes providing a biocompatible cartilage repair composition.In an embodiment, the composition includes amniotic tissue, a carrier ofa reverse phase mixture of poloxamer and water, wherein the compositionexhibits reverse phase behavior when the carrier is mixed with theamniotic tissue and is non-liquid at ambient and body temperatures. Thecomposition resists displacement at body temperatures. The methodincludes placing the composition in a cartilage defect of a mammal. Aprosthetic object can also be placed in the cartilage defect. The methodcan also comprise coating a portion of the prosthetic object with thebiocompatible composition, and in this embodiment the step of placingthe composition and the step of placing a prosthetic object can becontemporaneous.

MODES FOR CARRYING OUT VARIOUS EMBODIMENTS Definitions

By “reverse phase” or “reverse thermal behavior” is intended a materialthat exhibits a physical of becoming more viscous or solidifies uponimplantation in a cartilage defect of a mammal.

As used herein, “ambient temperature” is 25° C., plus or minus 5° C.

As used herein, “body temperature” is 37° C. plus or minus 5° C.

As used herein, a “cartilage defect” is an articulating cartilage of amammal which comprises some viable cartilage tissue. The defect can becongenital, caused by trauma, or caused by disease.

Examples

In an embodiment, the composition may be a flowable liquid when appliedto cartilage defect, whereupon the composition becomes increasinglysolidified or viscous as it warms from an ambient temperature (or frombelow ambient temperature) to the body temperature of the mammal. Uponbeing warmed to body temperature, the composition may be solid or highlyviscous and resistant to displacement due to synovial fluid. The reversephase compositions in accordance with the present disclosure aresignificantly different from cartilage repair materials in the prior artand do not function in the same way.

The composition may include a therapeutic material for treatingcartilage defects and a carrier. The therapeutic material can be amaterial that contains substantial number of growth factors needed incartilage regeneration. The carrier achieves reverse phasecharacteristics when mixed with the therapeutic material.

The therapeutic material can be a material, such as amniotic membrane,amniotic liquid, umbilical cord, or a combination thereof, that has asubstantial number of growth factors that are instrumental in cartilageregeneration. The therapeutic material may be provided in various sizedtissues, including substantially whole tissues to morcellated tissuesinto small pieces, liquid or a combination of solid tissue pieces withamniotic liquid components. As may be appreciated by one of ordinaryskill in the art, the therapeutic material can comprise combinations ofvarious therapeutic materials.

In one embodiment, the biocompatible carrier of the composition is amaterial that confers reverse phase thermodynamic properties on thecomposition. The use of PLURONIC® F127 as a component of anosteointegration promoting composition is set forth in U.S. Pat. No.5,503,558, issued Apr. 2, 1996 to the inventor herein, Cameron M. L.Clokie; and in PCT International Publication No. WO 95/13099. In apresently preferred embodiment, the carrier comprises a polymer marketedby BASF (Parsipanny, N.J.) as PLURONIC® F127. PLURONIC® F127 is apoly(oxyalkylene) block copolymer; more specifically, apoly(oxyethylene)-poly(oxypropylene)-poly(oxyethylene) triblockcopolymer; it is a member of a class of compounds called poloxamers.(Schmolka, “A Review of Block Polymer Surfactants” J. Am. Oil ChemistsSoc. 54:110-116 (1977)). Several members of the poloxamer family exhibitreverse phase thermodynamic characteristics. PLURONIC® F127 is alsoknown by the name “poloxamer 407.” (Schmolka, “A Comparison of BlockPolymer Surfactant Gels” J. Am. Oil Chemist Soc. 68:206-209 (1991)).PLURONIC® F127 has an average molecular weight of approximately 12,500.(Schmolka, “A Comparison of Block Polymer Surfactant Gels” J. Am. OilChemist Soc. 68:206-209 (1991)) The structure of the PLURONIC® F127polymer is depicted as follows:

In various embodiments of a composition of the present disclosure, thecarrier is a liquid diluted in a solvent or is a solid dispersed in asolvent. In one embodiment, PLURONIC® F127 is dispersed in a solventsuch as sterile water. The PLURONIC® F127 carrier is vastly different insize, molecular weight, and chemical structure than carriers in the art.The carrier is also substantially different in terms of its functionalproperties than any carrier of a cartilage repair material in the art.

The composition has a unique physical property for cartilage repair ofbeing flowable at refrigerated temperatures which will become viscous atbody temperature and will also be resistant to displacement afterimplantation. The unique reverse phase thermodynamic properties of thecomposition for cartilage repair allow various embodiments to functionin a substantially different and advantageous manner relative to otherflowable cartilage repair products. When applied to a cartilage defect,the reverse phase property of the preferred carrier provides supportcharacteristics for the composition which are substantially differentthan the characteristics of standard carriers. This is because thecomposition is flowable at room temperature and can be applied to acartilage defect, but becomes increasingly viscous and solidified oncewarmed at the defect site. The solidification of the composition of thepresent disclosure achieves several beneficial effects. When solidified,the composition does not flow away from the defect site, and thesolidified product immediately augments and facilitates therapeuticsupport at the site. Also, since the amniotic composition of the presentdisclosure is initially liquid, it readily fills the cartilage defect,then becomes solidified and achieves enhanced cartilage regeneration.

In another embodiment, a biocompatible articular cartilage tissue repaircomposition may include a reverse phase mixture of poloxamer andamniotic fluid. Water may or may not be a necessary component. Thecomposition is configured to exhibit reverse phase behavior and isnon-liquid at ambient and body temperatures. In an embodiment, thepoloxamer is poloxamer 407. The mixture of poloxamer and amniotic fluidmay be a provided in various ratios. In one embodiment, the mixture is25 percent weight poloxamer and 75 percent weight amniotic fluid. In anembodiment, the composition is 30 percent weight amniotic fluid and 70percent weight poloxamer. In another embodiment, the composition is 50percent weight amniotic fluid and 50 percent weight poloxamer.

For example, one carrier may be PLURONIC® F127 as the carrier in thecomposition of an embodiment of the composition. PLURONIC® F127 (whendispersed in an appropriate amount of sterile water) has the uniqueproperty of being a liquid at refrigerated temperature and increasinglysolidified, then solid at elevated temperature, absent the effects ofevaporation and concomitant loss of water. This property is called“reverse phase” or “reverse thermal behavior” because it is the exactopposite of the thermodynamic properties exhibited by standard carriers.

It is believed that the reverse phase property is due, at least in part,to the fact that PLURONIC® F127 is composed of discrete blocks of bothhydrophilic (i.e., oxyethylene) and hydrophobic (i.e., oxypropylene)subunits. (See e.g., Schmolka, “A Comparison of Block Polymer SurfactantGels” J. Am. Oil Chemist Soc. 68:206-209 (1991)).

In contrast, standard carriers, as well as all liquids, manifest thetypical physical property of becoming increasingly flowable uponaddition of thermal energy, such as occurs when the liquid is heated tobody temperature. However, the preferred carrier in a composition of thepresent invention becomes less flowable as energy is added to it eitherby heating or by shaking.

The unique reverse phase thermodynamic properties of the composition ofthe various embodiments herein allow the product to function in asubstantially different, and preferred manner relative to othercartilage repair products. When applied to a cartilage defect site, thereverse phase property of the carrier provides support characteristicsfor the composition which are substantially different than thecharacteristics of standard carriers. Enhanced support is provided bythe composition of various embodiments. In various embodiments, thePLURONIC® F127 carrier of the composition of one embodiment helps toprovide support characteristics which are unlike those of any standardcarrier. This is because the composition is flowable at refrigeratedtemperature and can thus readily be applied to a cartilage defect site,but it becomes increasingly viscous and solidified once it is warmed atthe site. The solidification of the composition of various embodimentsachieves several beneficial effects. When solidified, the compositiondoes not flow away from the defect site, and the solidified productimmediately augments and facilitates structural support at the defect.Also, since the cartilage regenerative composition is initially liquid,it readily fills a defect, then becomes solidified and achieves enhancedcartilage regeneration. Moreover, with various compositions comprising asterile aqueous colloidal suspension of PLURONIC® F127 as carrier andamniotic tissue, the carrier will resorb or dissolve after about threedays, leaving the amniotic tissue at the cartilage defect site. It isbelieved to be advantageous that the carrier disperses as this thenallows for enhanced ingrowth of connective or vascular tissues.

In a composition of various embodiments, the weight percentages of thetherapeutic material and the carrier can each be varied. For example,the weight percent of the therapeutic material can vary between about 20to 80 weight percent of the composition, and the weight percent of thecarrier can vary between about 20 to 80 weight percent of thecomposition. Furthermore one or more additional components can bepresent in a composition of various embodiments, such as antibiotics,analgesic, anti-inflammatory agents, or agents to promote development ofconnective or circulatory system tissues.

Although the above embodiments have been described in language that isspecific to certain structures, elements, compositions, andmethodological steps, it is to be understood that the technology definedin the appended claims is not necessarily limited to the specificstructures, elements, compositions and/or steps described. Rather, thespecific aspects and steps are described as forms of implementing theclaimed technology. Since many embodiments of the technology can bepracticed without departing from the spirit and scope of the invention,the invention resides in the claims hereinafter appended.

1-17. (canceled)
 18. A biocompatible articular cartilage tissue repaircomposition, comprising: components of amniotic tissue, and thecomponents of the amniotic tissue including at least one of cut amniotictissue, blended amniotic tissue, chopped amniotic tissue, and mixedamniotic tissue; and a reverse phase mixture of poloxamer and amnioticfluid, the reverse phase mixture configured as a carrier of the amniotictissue, and the carrier configured to resorb after a first period oftime at a cartilage defect site while leaving the amniotic tissue at thecartilage defect site to allow ingrowth of the amniotic tissue into thecartilage defect site; wherein the composition exhibits reverse phasebehavior, wherein the composition is non-liquid at ambient and bodytemperatures, and wherein the composition supports the amniotic tissuewith the carrier at the cartilage defect site for the first period oftime for the carrier to resorb.
 19. The composition of claim 18, whereinthe components of the amniotic tissue include growth factors configuredto regenerate cartilage at the cartilage defect site in an articulatingjoint containing synovial fluid.
 20. The composition of claim 19,wherein the composition further supports the amniotic tissue withingrowth during and subsequent to the first period of time so as tomaintain the growth factors configured to regenerate cartilage at thecartilage defect site for a second period of time, the second period oftime being longer than the first period of time, as the amniotic tissueis kept in place within the articulating joint containing synovialfluid.
 21. The composition of claim 18, wherein the poloxamer ispoloxamer
 407. 22. The composition of claim 18, wherein the mixture ofpoloxamer and amniotic fluid is 25 percent weight poloxamer and 75percent weight amniotic fluid.
 23. The composition of claim 18, whereinthe composition is 30 percent weight amniotic fluid and 70 percentweight poloxamer.
 24. The composition of claim 18, wherein thecomposition is 50 percent weight amniotic fluid and 50 percent weightpoloxamer.
 25. The composition of claim 18, wherein the amniotic tissueis xenogeneic, allogeneic or autogenic.
 26. A method to repair cartilagetissue, the method comprising: providing a biocompatible cartilagerepair composition, comprising: amniotic tissue, the amniotic tissueincluding at least one of cut amniotic tissue, blended amniotic tissue,chopped amniotic tissue, and mixed amniotic tissue, and a reverse phasemixture of poloxamer and a liquid, wherein the composition exhibitsreverse phase behavior and is non-liquid at ambient and bodytemperatures; and placing the composition in a cartilage defect of amammal.
 27. The method of claim 26, wherein the step of placing thecomposition in the cartilage defect of a mammal includes placing thecomposition in a liquid state at a given temperature below the ambientand body temperatures.
 28. The method of claim 26, wherein the step ofplacing the composition in the cartilage defect of a mammal includesallowing the composition to transition to a non-liquid at the ambientand body temperatures so as to resist displacement from the cartilagedefect.
 29. A biocompatible articular cartilage tissue repaircomposition, comprising: amniotic tissue, the amniotic tissue includingat least one of cut amniotic tissue, blended amniotic tissue, choppedamniotic tissue, and mixed amniotic tissue, and a reverse phase mixtureof poloxamer and amniotic fluid; wherein the composition exhibitsreverse phase behavior and is non-liquid at ambient and bodytemperatures.
 30. The composition of claim 29, wherein the amniotictissue includes growth factors configured to regenerate cartilage at thecartilage defect site in an articulating joint containing synovialfluid.
 31. The composition of claim 30, wherein the composition furthersupports the amniotic tissue with ingrowth so as to maintain the growthfactors configured to regenerate cartilage at the cartilage defect sitefor a period of time as the amniotic tissue is kept in place within thearticulating joint containing synovial fluid.
 32. The composition ofclaim 29, wherein the poloxamer is poloxamer
 407. 33. The composition ofclaim 29, wherein the mixture of poloxamer and amniotic fluid is 25percent weight poloxamer and 75 percent weight amniotic fluid.
 34. Thecomposition of claim 29, wherein the composition is 30 percent weightamniotic fluid and 70 percent weight poloxamer.
 35. The composition ofclaim 29, wherein the composition is 50 percent weight amniotic fluidand 50 percent weight poloxamer.
 36. The composition of claim 18,wherein the amniotic tissue is xenogeneic, allogeneic or autogenic.